Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5B9RKP)

• DOT Name: Alpha-2C adrenergic receptor (ADRA2C)
• Synonyms: Alpha-2 adrenergic receptor subtype C4; Alpha-2C adrenoreceptor; Alpha-2C adrenoceptor; Alpha-2CAR
• Gene Name: ADRA2C
• UniProt ID: ADA2C_HUMAN
• PDB ID: 6KUW
• Pfam ID: PF00001
• Sequence:
  MASPALAAALAVAAAAGPNASGAGERGSGGVANASGASWGPPRGQYSAGAVAGLAAVVGF
  LIVFTVVGNVLVVIAVLTSRALRAPQNLFLVSLASADILVATLVMPFSLANELMAYWYFG
  QVWCGVYLALDVLFCTSSIVHLCAISLDRYWSVTQAVEYNLKRTPRRVKATIVAVWLISA
  VISFPPLVSLYRQPDGAAYPQCGLNDETWYILSSCIGSFFAPCLIMGLVYARIYRVAKLR
  TRTLSEKRAPVGPDGASPTTENGLGAAAGAGENGHCAPPPADVEPDESSAAAERRRRRGA
  LRRGGRRRAGAEGGAGGADGQGAGPGAAESGALTASRSPGPGGRLSRASSRSVEFFLSRR
  RRARSSVCRRKVAQAREKRFTFVLAVVMGVFVLCWFPFFFSYSLYGICREACQVPGPLFK
  FFFWIGYCNSSLNPVIYTVFNQDFRRSFKHILFRRRRRGFRQ
• Function: Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  Adrenaline signalling through Alpha-2 adrenergic receptor (R-HSA-392023)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Surfactant metabolism (R-HSA-5683826)
  Adrenoceptors (R-HSA-390696)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]RX821002	DM6IRN4	Investigative	Alpha-2C adrenergic receptor (ADRA2C) affects the binding of [3H]RX821002.	[9]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Alpha-2C adrenergic receptor (ADRA2C).	[1]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[7]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[10]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of Alpha-2C adrenergic receptor (ADRA2C).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[4]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[13]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[14]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Alpha-2C adrenergic receptor (ADRA2C).	[15]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Oxymetazoline	DM8ZXT6	Approved	Oxymetazoline affects the binding of Alpha-2C adrenergic receptor (ADRA2C).	[9]
Xylometazoline	DMKV32D	Phase 4	Xylometazoline affects the binding of Alpha-2C adrenergic receptor (ADRA2C).	[9]
Phenethylamine	DMX0G4F	Investigative	Phenethylamine affects the binding of Alpha-2C adrenergic receptor (ADRA2C).	[16]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [8] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [9] Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline. Fundam Clin Pharmacol. 2010 Dec;24(6):729-39.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Characterization of the potent, selective Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017 Oct;363(1):114-125.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [15] Delocalization of Endogenous A-kinase Antagonizes Rap1-Rho-(2C)-Adrenoceptor Signaling in Human Microvascular Smooth Muscle Cells. J Cytol Mol Biol. 2014 Jan 10;1(1):1000002.
• [16] Effects of synephrine and beta-phenethylamine on human alpha-adrenoceptor subtypes. Planta Med. 2010 Jul;76(10):981-6. doi: 10.1055/s-0029-1240884. Epub 2010 Mar 9.